NQO2: A novel target to reduce oxidative stress in retinal pigment epithelium

描述（由申请人提供）：在美国，视网膜相关性黄斑变性（AMD）是55岁以上人群中不可逆失明的主要原因，也是慢性残疾的主要来源。然而，预防或减缓AMD进展的临床治疗选择非常有限。氧化应激诱导的视网膜色素上皮（RPE）损伤被认为与AMD的发展有关，我们实验室的初步数据表明，对酶N-核糖基-二氢烟酰胺（NRH）：醌氧化还原酶2（NQO 2）的药理学抑制可保护人RPE细胞免受这种氧化应激的影响。虽然一些证据表明参与抗氧化酶的诱导，这种保护的机制基本上是未知的。更好地理解NQO 2介导的保护机制对于开发针对AMD的适当治疗策略至关重要。在本申请中，我们假设NQO 2抑制介导抗氧化应激。其次，我们假设NQO 2抑制诱导抗氧化酶，这是对氧化应激的潜在保护机制。我们试图研究NQO 2抑制是否保护RPE细胞免受氧化应激（具体目的1）。我们还将研究NQO 2抑制对下游抗氧化酶（特异性目的2）表达的影响。该项目的长期目标是更好地了解参与氧化应激细胞防御机制的内源性途径，以确定临床相关靶点并降低RPE中的氧化应激。最终，我们希望找到有效的治疗方法来治疗AMD。 公共卫生相关性：老年人失明的主要原因是年龄相关性黄斑变性（AMD），但目前的治疗选择非常有限。由于眼睛中氧化剂引起的损伤被认为与AMD的发展有关，因此有效对抗氧化剂的治疗策略可能有助于减缓或预防AMD的进展。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the population over 55 years of age and a major source of chronic disability in the US. However, clinical treatment options that prevent or slow the progression of AMD are extremely limited. Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is thought to be involved in the development of AMD, and preliminary data from our lab suggests that pharmacological inhibition of the enzyme, N-ribosyl-dihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2), protects human RPE cells from this oxidative stress. While some evidence suggests involvement of antioxidant enzyme induction, the mechanism of this protection is essentially unknown. A better understanding of the mechanism of NQO2-mediated protection is crucial to developing appropriate therapeutic strategies against AMD. In this application, we hypothesize that NQO2 inhibition mediates the resistance against oxidative stress. Secondly, we hypothesize that NQO2 inhibition induces antioxidant enzymes, which is the underlying protective mechanism against oxidative stress. We seek to investigate whether NQO2 inhibition protects RPE cells from oxidative stress (Specific Aim 1). We will also investigate the effect of NQO2 inhibition on the expression of downstream antioxidant enzymes (Specific Aim 2). The long-term goal of this project is to better understand the endogenous pathways involved in the cellular defense mechanisms against oxidative stress in order to determine clinically relevant targets and reduce oxidative stress in the RPE. Ultimately, we hope to identify effective therapeutic approaches to AMD. PUBLIC HEALTH RELEVANCE: The leading cause of blindness in the elderly is age-related macular degeneration (AMD), but current treatment options are extremely limited. Because the damage caused by oxidants in the eye is thought to be involved in the development of AMD, treatment strategies effectively countering oxidants may help slow or prevent the progression of AMD.